S118: A CHEMOTHERAPY-FREE COMBINATION OF PONATINIB AND BLINATUMOMAB FOR PATIENTS WITH NEWLY DIAGNOSED PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA: SUBGROUP ANALYSIS FROM A PHASE II STUDY
Authors: Nicholas Short, Elias Jabbour, Nitin Jain, Xuelin Huang, Walid Macaron, Lewis Nasr, Guillermo Montalban-Bravo, Tapan Kadia, Naval Daver, Kelly Chien, Yesid Alvarado, Ghayas Issa, Fadi Haddad, Cedric Nasnas, Marianne Zoghbi, Rebecca Garris, Marina Konopleva, Farhad Ravandi, Hagop Kantarjian
Journal: HemaSphere (2023)

Background: Ponatinib and blinatumomab are both active in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The combination of these two drugs could offer an effective chemotherapy-free strategy for patients (pts) with Ph+ ALL and reduce the need for allogeneic stem cell transplantation (SCT). Aims: We evaluated the chemotherapy-free approach of ponatinib and blinatumomab in patients with newly diagnosed Ph+ ALL. The primary endpoint was the complete molecular response (CMR) rate. Methods: In this phase II study, pts ≥18 years of age with newly diagnosed Ph+ ALL were eligible. Pts who had received 1-2 previous cycles of chemotherapy, with or without a BCR::ABL1 TKI, could still be enrolled. Pts were required to have a performance status of ≤2, total bilirubin ≤2x the upper limit of normal (ULN), and ALT and AST ≤3x the ULN. Pts with uncontrolled cardiovascular disease or clinically significant central nervous system (CNS) comorbidities (except for CNS leukemia) were excluded. Pts received up to 5 cycles of blinatumomab as a continuous infusion at standard doses. Ponatinib 30mg daily was started during cycle 1 and was decreased to 15mg daily once CMR was achieved. After 5 cycles of blinatumomab, ponatinib was continued for at least 5 years. Twelve doses of prophylactic IT chemotherapy with alternating cytarabine and methotrexate were administered. Results: Between June 2018 to January 2023, 54 pts with newly diagnosed Ph+ ALL were enrolled. Baseline characteristics are shown in Table 1. 19 pts were in CR at enrollment (5 of whom were in CMR and were evaluable only for relapse and survival outcomes). Among the 35 pts who were evaluable for hematologic response, 34 (97%) achieved CR or CRi, with CR achieved in 33 pts (94%). There was 1 early death (intracranial hemorrhage on day 18). All hematologic responses occurred after 1 cycle. Among the 48 pts evaluable for CMR, 34 pts (71%) achieved CMR after cycle 1, and 43 pts (90%) achieved CMR at any time. After only 2 weeks of therapy, 14 of 24 pts (58%) with active disease at enrollment achieved CMR in the peripheral blood. Thirty-four of 38 tested pts (89%) also became MRD-negative by an NGS assay with sensitivity of 1x10-6 (clonoSEQ assay from Adaptive Biotechnologies Co.). Four of these 34 pts (12%) who were MRD-negative by NGS had detectable low-level BCR::ABL1 transcripts by PCR at the same time (ranging from 0.01% to 0.05%). Among 53 patients who received at least 1 complete cycle of ponatinib plus blinatumomab, there were 2 deaths in CR (1 due to hypovolemic shock following cardiac catheterization and 1 due to brain aneurysm). Three patients relapsed after a median of 9 months from response (2 extramedullary and 1 bone marrow relapse), and 48 pts are in ongoing hematologic remission. Only 1 pt underwent SCT in first remission; this pt was transplanted due to persistently detectable BCR::ABL1 transcripts of 0.01%-0.05%. The median follow-up is 16 months (range, 1-55 months). The estimated 2-year EFS is 80% and 2-year OS is 90% (Figure 1). No leukemia-related deaths have occurred. Most toxicities were grade 1-2 and consistent with the known toxicities of the two agents. There were no grade 4-5 related adverse events. Ponatinib was discontinued in 2 patients due to possibly related adverse events (CVA and coronary stenosis in 1 pt each). Summary/Conclusion: The chemotherapy-free combination of ponatinib and blinatumomab results in high rates of CMR and NGS MRD negativity. Encouraging duration of remission and survival has been observed without the need for SCT.Keywords: Acute lymphoblastic leukemia, Clinical trial, Ph+ ALL